ABSTRACT The overall goal of this proposal is to further our understanding of the molecular mechanisms governing hepatocyte proliferation in response to liver injury. Various insults including hepatotoxins, drug toxicity, and viral infection cause acute or chronic liver injury. However, the liver has an extraordinary ability to regenerate, replacing damaged tissue and restoring original structures and functions. Hepatocytes, as the main structural and functional cells in the liver, are extremely capable of replicating during liver tissue repair process. Remarkably, hepatocyte proliferation constitutes the fundamental process of liver regeneration. Timely and/or enhanced hepatocyte proliferation leads to recovery from liver injury and survival, whereas delayed and/or inhibited hepatocyte proliferation in pathological conditions results in liver failure and death. Therefore, understanding the regulation of hepatocyte proliferation is of particular importance in developing therapeutic means targeting liver tissue repair for prevention and treatment of liver injury. Forming a complex regulatory network, various growth factors and cytokines participate in modulating the proliferative process of hepatocytes. However, the precise molecular mechanisms that control hepatocyte proliferation in response to liver injury remain poorly defined. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a transcription factor that plays a central role in regulating the transcription of genes encoding drug-detoxifying enzymes and antioxidant proteins. Our preliminary studies revealed that Nrf2 activation stimulates hepatocyte proliferation, which represents a novel function of this transcription factor. Furthermore, our preliminary studies demonstrated that Nrf2 is highly activated during partial hepatectomy (PH)-induced liver regeneration and lack of Nrf2 leads to severely suppressed liver growth after PH. These findings suggest that Nrf2 participates in modulating hepatocyte proliferation in response to liver mass loss. Therefore, our central hypothesis is that Nrf2 participates in regulating hepatocyte proliferation during liver regeneration. To test this hypothesis, two specific aims are proposed. Specific Aim 1: determine the molecular mechanisms by which Nrf2 regulates hepatocyte proliferation. Specific Aim 2: determine the effects of pharmacological activation of Nrf2 on hepatocyte proliferation and liver growth during liver regeneration. The proposed investigation will enable us to gain greater insight into the mechanisms governing hepatocyte proliferation during liver regeneration. Moreover, the proposed studies will establish the novel function of Nrf2 in regulating hepatocyte proliferation. Furthermore, our proposed studies will provide essential information to evaluate Nrf2 as a novel target for treatment of liver injury through a mechanism of enhancing liver repair.